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A TRPA1-dependent mechanism for the pungent sensation of weak acids.

Wang YY, Chang RB, Allgood SD, Silver WL, Liman ER - J. Gen. Physiol. (2011)

Bottom Line: Our results show that heterologously expressed TRPA1 currents can be induced by a series of weak organic acids, including acetic, propionic, formic, and lactic acid, but not by strong acids.Importantly, responses of trigeminal neurons to weak acids were highly overrepresented in the subpopulation of TRPA1-expressing neurons and were severely reduced in neurons from TRPA1 knockout mice.We conclude that TRPA1 is a general sensor for weak acids that produce intracellular acidification and suggest that it functions within the pain pathway to mediate sensitivity to cellular acidosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, Section of Neurobiology, University of Southern California, Los Angeles, CA 90089, USA.

ABSTRACT
Acetic acid produces an irritating sensation that can be attributed to activation of nociceptors within the trigeminal ganglion that innervate the nasal or oral cavities. These sensory neurons sense a diverse array of noxious agents in the environment, allowing animals to actively avoid tissue damage. Although receptor mechanisms have been identified for many noxious chemicals, the mechanisms by which animals detect weak acids, such as acetic acid, are less well understood. Weak acids are only partially dissociated at neutral pH and, as such, some can cross the cell membrane, acidifying the cell cytosol. The nociceptor ion channel TRPA1 is activated by CO(2), through gating of the channel by intracellular protons, making it a candidate to more generally mediate sensory responses to weak acids. To test this possibility, we measured responses to weak acids from heterologously expressed TRPA1 channels and trigeminal neurons with patch clamp recording and Ca(2+) microfluorometry. Our results show that heterologously expressed TRPA1 currents can be induced by a series of weak organic acids, including acetic, propionic, formic, and lactic acid, but not by strong acids. Notably, the degree of channel activation was predicted by the degree of intracellular acidification produced by each acid, suggesting that intracellular protons are the proximate stimulus that gates the channel. Responses to weak acids produced a Ca(2+)-independent inactivation that precluded further activation by weak acids or reactive chemicals, whereas preactivation by reactive electrophiles sensitized TRPA1 channels to weak acids. Importantly, responses of trigeminal neurons to weak acids were highly overrepresented in the subpopulation of TRPA1-expressing neurons and were severely reduced in neurons from TRPA1 knockout mice. We conclude that TRPA1 is a general sensor for weak acids that produce intracellular acidification and suggest that it functions within the pain pathway to mediate sensitivity to cellular acidosis.

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Lactic acid and MO act in synergy to activate TRPA1. (A) 20 mM lactic acid, pH 5, activated small TRPA1 currents in TRPA1-expressing HEK-293 cells (top). The addition of extracellular Ca2+ produced no enhancement of activation by lactic acid (bottom). (B) Preexposure to MO greatly increased TRPA1 current activation in response to lactic acid. (C) Average data from experiments as in A and B. Data are represented by the mean ± SEM. Significance was determined with the two-tailed Student’s t test. *, P < 0.05; **, P < 0.01.
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fig7: Lactic acid and MO act in synergy to activate TRPA1. (A) 20 mM lactic acid, pH 5, activated small TRPA1 currents in TRPA1-expressing HEK-293 cells (top). The addition of extracellular Ca2+ produced no enhancement of activation by lactic acid (bottom). (B) Preexposure to MO greatly increased TRPA1 current activation in response to lactic acid. (C) Average data from experiments as in A and B. Data are represented by the mean ± SEM. Significance was determined with the two-tailed Student’s t test. *, P < 0.05; **, P < 0.01.

Mentions: Previous experiments have shown that exposure to reactive electrophiles sensitizes TRPA1 channel to activation by cold temperature (del Camino et al., 2010). TRPA1 was only modestly activated by some physiologically relevant weak acids, including lactic acid, even in the presence of extracellular Ca2+ (Fig. 7, A and C), raising the possibility that responses to these acids might be unmasked by preactivation with reactive electrophiles. To test this possibility, we activated cells either with 20 mM of lactic acid or with 20 mM of lactic acid after preactivation with 25 µM MO in the absence of extracellular Ca2+. Responses to lactic acid were significantly larger after preactivation with MO (Fig. 7, B and C), suggesting that reactive electrophiles sensitize TRPA1 to activation by weak acids.


A TRPA1-dependent mechanism for the pungent sensation of weak acids.

Wang YY, Chang RB, Allgood SD, Silver WL, Liman ER - J. Gen. Physiol. (2011)

Lactic acid and MO act in synergy to activate TRPA1. (A) 20 mM lactic acid, pH 5, activated small TRPA1 currents in TRPA1-expressing HEK-293 cells (top). The addition of extracellular Ca2+ produced no enhancement of activation by lactic acid (bottom). (B) Preexposure to MO greatly increased TRPA1 current activation in response to lactic acid. (C) Average data from experiments as in A and B. Data are represented by the mean ± SEM. Significance was determined with the two-tailed Student’s t test. *, P < 0.05; **, P < 0.01.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3105510&req=5

fig7: Lactic acid and MO act in synergy to activate TRPA1. (A) 20 mM lactic acid, pH 5, activated small TRPA1 currents in TRPA1-expressing HEK-293 cells (top). The addition of extracellular Ca2+ produced no enhancement of activation by lactic acid (bottom). (B) Preexposure to MO greatly increased TRPA1 current activation in response to lactic acid. (C) Average data from experiments as in A and B. Data are represented by the mean ± SEM. Significance was determined with the two-tailed Student’s t test. *, P < 0.05; **, P < 0.01.
Mentions: Previous experiments have shown that exposure to reactive electrophiles sensitizes TRPA1 channel to activation by cold temperature (del Camino et al., 2010). TRPA1 was only modestly activated by some physiologically relevant weak acids, including lactic acid, even in the presence of extracellular Ca2+ (Fig. 7, A and C), raising the possibility that responses to these acids might be unmasked by preactivation with reactive electrophiles. To test this possibility, we activated cells either with 20 mM of lactic acid or with 20 mM of lactic acid after preactivation with 25 µM MO in the absence of extracellular Ca2+. Responses to lactic acid were significantly larger after preactivation with MO (Fig. 7, B and C), suggesting that reactive electrophiles sensitize TRPA1 to activation by weak acids.

Bottom Line: Our results show that heterologously expressed TRPA1 currents can be induced by a series of weak organic acids, including acetic, propionic, formic, and lactic acid, but not by strong acids.Importantly, responses of trigeminal neurons to weak acids were highly overrepresented in the subpopulation of TRPA1-expressing neurons and were severely reduced in neurons from TRPA1 knockout mice.We conclude that TRPA1 is a general sensor for weak acids that produce intracellular acidification and suggest that it functions within the pain pathway to mediate sensitivity to cellular acidosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Sciences, Section of Neurobiology, University of Southern California, Los Angeles, CA 90089, USA.

ABSTRACT
Acetic acid produces an irritating sensation that can be attributed to activation of nociceptors within the trigeminal ganglion that innervate the nasal or oral cavities. These sensory neurons sense a diverse array of noxious agents in the environment, allowing animals to actively avoid tissue damage. Although receptor mechanisms have been identified for many noxious chemicals, the mechanisms by which animals detect weak acids, such as acetic acid, are less well understood. Weak acids are only partially dissociated at neutral pH and, as such, some can cross the cell membrane, acidifying the cell cytosol. The nociceptor ion channel TRPA1 is activated by CO(2), through gating of the channel by intracellular protons, making it a candidate to more generally mediate sensory responses to weak acids. To test this possibility, we measured responses to weak acids from heterologously expressed TRPA1 channels and trigeminal neurons with patch clamp recording and Ca(2+) microfluorometry. Our results show that heterologously expressed TRPA1 currents can be induced by a series of weak organic acids, including acetic, propionic, formic, and lactic acid, but not by strong acids. Notably, the degree of channel activation was predicted by the degree of intracellular acidification produced by each acid, suggesting that intracellular protons are the proximate stimulus that gates the channel. Responses to weak acids produced a Ca(2+)-independent inactivation that precluded further activation by weak acids or reactive chemicals, whereas preactivation by reactive electrophiles sensitized TRPA1 channels to weak acids. Importantly, responses of trigeminal neurons to weak acids were highly overrepresented in the subpopulation of TRPA1-expressing neurons and were severely reduced in neurons from TRPA1 knockout mice. We conclude that TRPA1 is a general sensor for weak acids that produce intracellular acidification and suggest that it functions within the pain pathway to mediate sensitivity to cellular acidosis.

Show MeSH
Related in: MedlinePlus